The liver has a predominate role in fat metabolism and normally accumulates lipids (fat), but only to “normal levels.” Excessive lipid accumulation in hepatocytes results in hepatic steatosis, which is metabolically harmful and can result from a variety of liver dysfunctions, such as decreased beta-oxidation or decreased secretion of lipoproteins. Another of the many functions of the liver is to release glucose into the circulation. In healthy individuals, liver cells release glucose regularly to regulate blood glucose levels. In contrast, in individuals with diabetes, liver cells release glucose uncontrollably, which increases blood glucose levels. Therefore, reducing glucose release from liver cells (hepatocytes) can be very effective in controlling diabetes.
Excessive lipid accumulation in the liver may contribute to insulin resistance, and thus poor glycemic control. Adiponectin, a protein secreted by fat tissue (adipose tissue) improves insulin sensitivity in many ways. Adiponectin acts via adiponectin receptors AdipoR1 and AdipoR2 to activate AMPK and PPARα pathways (32), to decrease systemic and hepatic insulin resistance, and to attenuate liver inflammation and fibrosis (32). It is a strong determinant of hepatic lipid content, as indicated by mice models of adiponectin KO or overexpression (14, 33). Adiponectin lowers hepatic steatosis by the up-regulation of AMPK-mediated hepatic lipid oxidation (34).
Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of adults in the U.S., and includes the excessive accumulation of fat in the liver (hepatic steatosis). It is often associated with obesity and insulin resistance (1, 2). The prevalence of NAFLD is about 70-80% in adults with type 2 diabetes or obesity (3-5), 3-10%, in all children, and up to 40-70% in obese children (4). NAFLD is associated with greater overall and liver-related mortality (6, 7). In addition to steatosis, inflammation and fibrosis can develop and NAFLD may progress to non-alcoholic steato-hepatitis (NASH), cirrhosis, liver failure and hepatocellular carcinoma. While steatosis is potentially reversible, once it progresses to NASH, there are no established treatments, and the few available medications show limited success (8, 9). Therefore, the timely prevention and/or treatment of hepatic steatosis is critical. However, even for NAFLD, drug treatment has marginal success (10), and reducing dietary fat intake and obesity are the mainstay of treatment (11). Despite the obvious health benefits, compliance with lifestyle changes to achieve sustained improvements in diet or obesity has proved challenging for the general population.
While excess adiposity or a high fat (HF)-diet are risk factors for NAFLD, Adenovirus 36 (Ad36) attenuates hepatic steatosis in mice despite a continued HF-diet and without a reduction in visceral or subcutaneous adiposity. Ad36 appears to qualitatively engineer existing adipose tissue to attenuate HF-diet induced hepatic steatosis. This change in metabolic quality of adipose tissue by Ad36 includes greater uptake and reduced release of fatty acids and greater adiponectin secretion (12, 13). This unique capability of Ad36 offers a remarkable model to creatively negate the ill effects of excess adiposity or excess dietary fat intake, without the need to reduce it. Thiazolidinediones (TZDs) class of drugs can also improve metabolic quality of adipose tissue, up-regulate adiponectin, and improve hepatic steatosis (14-16). Serious side effects of TZDs have been reported (17-19).
Ad36 does not cause morbidity or unintended mortality in animals. In addition, Ad36 appears to have distinct advantages over the action of the TZDs, particularly in the presence of a HF-diet. Unlike the TZDs Ad36 does not increase adiposity in HF-fed mice (20, 21). In the presence of a HF-diet, TZDs can improve glycemic control, but they concurrently promote lipid storage in various organs, including the liver (20, 22, 23). This limits the scope of TZDs, if fat intake is not reduced. Due to its dietary-fat and adiposity-independent effects, potential action of Ad36 on multiple metabolic pathways may offer a novel anti-steatosis approach that is clinically more attractive, and, therefore, potentially more effective.
Harnessing certain properties of viruses for beneficial purposes has been creatively used for several years, including the use of bactericidal properties of a bacteriophage virus (27), the oncolytic ability of a mutant adenovirus (28), or the use of Herpes simplex virus and several other viruses for the treatment of cancers (29), alone, or with various synergistic drugs (30, 31).
Therefore, agents to lower hepatic steatosis independent of adiposity or dietary fat intake would be extremely attractive and of practical benefit.